Systemic immune-inflammation mediates the association between Klotho protein and metabolic syndrome: findings from a large-scale population-based study.

BACKGROUND: This study utilized large-scale population data from the National Health and Nutrition Examination Survey (NHANES) to elucidate the relationship between the Klotho protein and metabolic syndrome along with its components. We further investigated the possible mediating effect of inflammation on these relationships. Our objective was to identify biomarkers for risk stratification and potential therapeutic targets for metabolic syndrome. METHODS: This study enrolled 13,119 participants aged 40-79 years, spanning five NHANES cycles from 2007 to 2016, with complete information on metabolic syndrome and the Klotho protein. The definition of metabolic syndrome followed the criteria of the National Cholesterol Education Program-Adult Treatment Panel III. Survey-weighted logistic regression and subgroup analysis were used to explore the associations between serum Klotho protein levels and metabolic syndrome, along with its components. Mediation analysis was performed to investigate the mediating effects of inflammation-related markers, including white blood cells, neutrophils, lymphocytes, monocytes, the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII) and the monocyte-to-HDL ratio (MHR), with the aim of elucidating how the Klotho protein influences the onset and progression of metabolic syndrome. RESULTS: The study participants had an average age of 56.06 years (95% CI: 55.76-56.37), with a Klotho protein concentration of 798.10 pg/ml (95% CI: 656.50-980.50) and a 43.77% prevalence of metabolic syndrome (n = 5742). In the crude model, Klotho was negatively correlated with metabolic syndrome and its components, including central obesity, hypertension, and hypertriglyceridemia. After adjusting for all confounding factors, Klotho was demonstrated to be negatively associated only with metabolic syndrome (OR: 0.82, 95% CI: 0.70-0.97), hypertension (OR: 0.83, 95% CI: 0.70-0.98), and hypertriglyceridemia (OR: 0.78, 95% CI: 0.67-0.91). Subgroup and interaction analyses revealed significant interactions between age, sex, race/ethnicity, body mass index, and Klotho. Additionally, mediation analysis demonstrated that leukocytes, neutrophils and monocytes accounted for 34.78%, 31.91% and 7.13%, respectively, of the associations between Klotho and metabolic syndrome. CONCLUSION: The serum concentration of Klotho protein was negatively associated with metabolic syndrome, with the relationship being partly mediated by systemic immune inflammation. The findings of this research revealed that the Klotho protein may be a valuable biomarker for risk stratification and a potential therapeutic target for metabolic syndrome.

Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells.

Klotho is an anti-aging protein produced primarily by tubular epithelial cells (TECs). Down-regulated expression of Klotho in injured TECs plays a key pathogenic role in promoting acute kidney injury (AKI) to chronic kidney disease (CKD) transition, yet therapeutic approaches targeting the restoration of renal Klotho levels remain challenging for clinical application. Here, we synthesize polydopamine-polyethylenimine-l-serine-Klotho plasmid nanoparticles (PPSK NPs), which can safely and selectively deliver the Klotho gene to the injured TECs through binding kidney injury molecule-1 and maintain the expression of Klotho protein. In vitro, PPSK NPs effectively reduce the hypoxia-reoxygenation-induced reactive oxygen species production and fibrotic gene expression. In the unilateral ischemia-reperfusion injury- and folic acid-induced AKI-CKD transition mouse models, a single low-dose injection of PPSK NPs is sufficient to preserve the normal kidney architecture and prevent renal fibrosis. Mechanismly, the protective effect of PPSK NPs relies on upregulating a key molecule peroxisome proliferator-activated receptor alpha (PPARα) via the inhibition of p38 and JNK phosphorylation, which in turn improves tubular fatty acid beta-oxidation and reduces renal lipid accumulation, thereby protecting against kidney fibrosis. In conclusion, our results highlight the translational potential of nanoparticle-based Klotho gene therapy in preventing the AKI-CKD transition.

Uric acid mediates the association between testosterone and α-Klotho among males: results from the NHANES 2013-2016.

PURPOSE: This study initially conducted a cross-sectional analysis to examine the association between total testosterone (TT), uric acid, and Klotho. The investigation examined whether uric acid mediates the association between TT and Klotho in males. METHODS: Based on data from the National Health and Nutrition Examination Survey (NHANES) 2013-2016, this study performed weighted multivariable-adjusted linear regression to evaluate the association between TT, uric acid, and α-Klotho. Then, mediation analysis was conducted to delineate the potential mediating role of uric acid in the TT-Klotho association. RESULTS: Multivariable linear regression analyses revealed inverse relationships between TT and uric acid (ß = - 2.75, 95% CI: - 4.21, 1.28, p < 0.001) and between uric acid and α-Klotho (ß = - 4.80, 95% CI: - 6.47, - 3.13, p < 0.001). Conversely, a positive correlation existed between TT and α-Klotho (ß = 5.38, 95% CI: 2.23, 8.53, p < 0.001). Updated subgroup analyses show that the association strength between α-Klotho, TT, and uric acid levels was consistent across various population settings without significant variations. Restricted cubic spline analysis identified a non-linear association between TT and uric acid with an inflection point at 201 ng/mL. Mediation analysis confirmed uric acid-mediated 18.59% of the association between TT and α-Klotho (p < 0.001), highlighting its significant intermediary role. CONCLUSION: This study elucidates the complex interrelationship between TT, uric acid, and α-Klotho, highlighting uric acid's significant mediating role. These findings provide novel insights into the hormonal and metabolic mechanisms underlying age-related processes and longevity.

The association between the triglyceride-glucose index and serum anti-aging protein α- Klotho: a population-based study.

BACKGROUND: Both anti-aging protein α-Klotho and the triglyceride-glucose (TyG) index hold predictive value for the incidence, progression, and outcomes of cardiovascular disease, diabetes and many other diseases. However, their relationship remains unclear. METHODS: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Weighted multivariate linear regression models and subgroup analysis were constructed to assess the association between TyG index and α-Klotho levels. Nonlinear correlations were explored using restricted cubic splines (RCS), generalized additive models (GAM) and smooth curve fitting. Segmented regression model was conducted to explore potential threshold effects and identify the inflection point. RESULTS: A total of 2568 participants satisfied the predetermined criteria were enrolled in the final analysis. After fully adjusting for covariates, TyG index was shown to be markedly negatively correlated with α-Klotho [ß=-74.07, 95%CI (-100.29,-47.85), p < 0.001]. Gender was significantly correlated with this negative connection according to subgroup analysis and interaction testing (p for interaction < 0.05).Additionally, we discovered a linear association between TyG index and α-Klotho in all participants (p for nonlinear = 0.761), while non-linear association in female (p for nonlinear = 0.016).The analysis of threshold effect in the female participants found that the inflection point of TyG index was 8.01, exceed which the level of α-Klotho decreased significantly with increasing TyG index[ß=-151.72, 95%CI (-201.93, -101.50), p < 0.001]. CONCLUSION: Our findings demonstrate a negative association between TyG index and α-Klotho levels, with the effect being more pronounced in females. TyG index may serve as an early indicator of individuals with low α-Klotho levels, especially among females. These findings highlight the need for gender-specific considerations in clinical interventions to improve public health. Further research is needed to clarify the causal direction of this association.

The FGF23-Klotho axis promotes microinflammation in chronic kidney disease.

The management of chronic kidney disease (CKD) is a global health challenge. Elevated levels of inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), are associated with higher mortality rates in patients with CKD. Moreover, increased fibroblast growth factor 23 (FGF23) levels are a strong predictor of adverse clinical outcomes in CKD. The production of Klotho, which plays a protective role is decreased in patients with CKD. However, the relationship between FGF23-Klotho and levels of inflammatory factors in patients with CKD is unclear. This study aimed to explore the effects of changes in the FGF23-Klotho axis on inflammatory factors in patients with CKD, with a view to providing ideas for novel treatments of CKD. Clinical data were collected from 85 patients with CKD and 17 healthy subjects admitted to the Department of Nephrology of Henan Provincial People's Hospital between June-August 2023. The differences in biochemical indicators at various stages of CKD and healthy people were analyzed. Using enzyme-linked immunosorbent assay and immunohistochemistry, changes in the FGF23-Klotho axis, and their relationship with interleukin 6 (IL-6) and TNF-α were assessed. FGF23 levels gradually increased from CKD stages 1 to 5, with significant differences observed between stages 3 to 5. Klotho levels significantly decreased in CKD stages 3-5. The levels of C-reactive protein (CRP), IL-6, and TNF-α gradually increased. Overall, FGF23 expression was negatively correlated with Klotho levels and positively correlated with CRP, IL-6, and TNF-α levels. In renal tubular epithelial cells, knockdown of Klotho and overexpression of FGF23 increased the expression of inflammatory factors; however, their levels were significantly lower than that of the Klotho knockdown group. Collectively, these findings demonstrate that in CKD, the FGF23-Klotho axis promotes the expression of inflammatory cytokines in renal tubular epithelial cells.

Involvement of Single Nucleotide Variants in the Klotho Gene Among Obesity Individuals with and without Type 2 Diabetes Mellitus in the Saudi Population.

Purpose: Aging is characterized by the gradual physiological changes and alterations that accumulate over time in the human body. The combination of obesity and ageing can lead to an increased risk of serious health issues or death. Single nucleotide variants (SNVs) in the Klotho gene were commonly studied, including that in type 2 diabetes mellitus (T2DM). Aim: The aim of this study is to examine the possible effect of SNVs in Klotho on the obese population in Saudi Arabia using middle-aged participants with and without T2DM. Methods: This study consists of 100 controls and 100 obesity patients, in which 50 had T2DM and the remaining 50 were obese without T2DM. Genotyping was performed with PCR, and Sanger sequencing analysis was used to validate the molecular association. Results: In this study, rs1207568 (p = 0.001-0.003) and rs9527025 (p = 0.001-0.00004) SNVs were associated with obesity cases. However, none of the genotypes or allele frequencies showed a positive association with the rs564481 SNV (p = 0.344-0.881). The multiple linear regression model showed that waist and hip were associated (p = 0.01-0.02). ANOVA analysis showed age (p = 0.04), hip (p = 0.002), SBP, and TC (p = 0.02) were associated. Finally, SNV (rs1207568 and rs95270250) and obesity (p < 0.001) associations were confirmed through gene multifactor dimensionality reduction analysis with gene-gene interaction, dendrogram, and graphical depletion method. Conclusion: This study concludes that rs1207568 and rs9527025 SNVs are associated with obesity in the Saudi population. Additional genetical statistics showed significant association between dependent and independent variables. SNVs in Klotho play a role in the Saudi population's susceptibility to obesity.

Current cigarette smoking and decreased serum levels of α-Klotho, an anti-aging hormone, among US adult participants.

BACKGROUND AND AIMS: Cigarette smoking is a well-established risk factor for cardiovascular disease and other aging-related disorders; yet the pathogenesis of these diseases induced by smoking remains relatively underexplored. This study was to assess the association between cigarette smoking and serum α-Klotho levels, an anti-aging protein, in US adults. METHODS AND RESULTS: Data on 4196 participants aged 40-79 years from the 2013-2016 National Health and Nutrition Examination Survey was analyzed for the association using multiple general linear models. Smoking was assessed using both questionnaire data and serum cotinine measurements. Both past and current smokers exhibited significantly lower levels of α-Klotho, with the light smokers exhibiting the lowest levels [geometric mean: 720.85 pg/mL; 95% CI: 662.53, 784.31], compared with non-smokers [806.75 (790.69, 823.13)]. A significantly inverse association between current smoking and α-Klotho levels was revealed. This relationship extended across smoking intensities, with even light smokers displaying the strongest association. After adjusting for potential confounders, light (smoked <5 pack-years), moderate (5-19 pack-years), and heavy smoking (≥20 pack-years) were associated with reductions of 10.81% (-16.91, -4.28), 6.43% (-10.24, -2.47), and 3.38% (-6.83, 0.19) of Klotho levels, respectively, when compared to non-smoking. Active smoking, defined as serum cotinine levels ≥10 ng/mL, was associated with a 4.59% decrease (-6.91, -2.23) in α-Klotho levels. CONCLUSION: The study demonstrates an inverse relationship between current smoking and serum α-Klotho levels among middle-aged and older adults. Our findings suggest that Klotho may play an important role in smoking-induced diseases. Further investigations are warranted to explore these interactions.

Distinct role of Klotho in long bone and craniofacial bone: skeletal development, repair and regeneration.

Bone defects are highly prevalent diseases caused by trauma, tumors, inflammation, congenital malformations and endocrine abnormalities. Ideally effective and side effect free approach to dealing with bone defects remains a clinical conundrum. Klotho is an important protein, which plays an essential role in regulating aging and mineral ion homeostasis. More recently, research revealed the function of Klotho in regulating skeleton development and regeneration. Klotho has been identified in mesenchymal stem cells, osteoblasts, osteocytes and osteoclasts in different skeleton regions. The specific function and regulatory mechanisms of Klotho in long bone and craniofacial bone vary due to their different embryonic development, ossification and cell types, which remain unclear and without conclusion. Moreover, studies have confirmed that Klotho is a multifunctional protein that can inhibit inflammation, resist cancer and regulate the endocrine system, which may further accentuate the potential of Klotho to be the ideal molecule in inducing bone restoration clinically. Besides, as an endogenous protein, Klotho has a promising potential for clinical therapy without side effects. In the current review, we summarized the specific function of Klotho in long bone and craniofacial skeleton from phenotype to cellular alternation and signaling pathway. Moreover, we illustrated the possible future clinical application for Klotho. Further research on Klotho might help to solve the existing clinical difficulties in bone healing and increase the life quality of patients with bone injury and the elderly.

Serum alpha klotho levels in Parkinson's Disease.

PURPOSE: Parkinson's Disease (PD), a neurodegenerative disorder, is associated with substantial morbidity. α-Klotho, an anti-aging protein known for its neuroprotective properties, has gained attention. This study aims to assess serum levels of α-Klotho in PD patients. METHODS: This study is a cross-sectional case-control study. PD was diagnosed according to UK Parkinson Disease Society Brain Bank criteria. Serum α-Klotho level was measured using a commercially available enzyme-linked immunosorbent assay. RESULTS: Of the 314 participants in the study, 157 were patients with PD and 157 were controls. Lower levels of α-Klotho were observed in PD (0.85 nmol/L) in comparison to the controls (1.47 nmol/L, p < 0.001). α-Klotho levels were also significantly lower among PD patients with dementia compared to PD patients without dementia. In logistic regression analysis, α-Klotho (OR: 0.04, p < 0.001) demonstrated a significant relationship between PD. A significant correlation was identified between α-Klotho levels and Mini-Mental State Examination scores in PD patients. The sensitivity and the specifity of α-Klotho were 90% and 65% for predicting PD. CONCLUSIONS: Our findings suggest that α-klotho could potentially serve as a biomarker. However additional studies are needed to confirm our findings.

Exploring the Link between Serum Klotho and High-Frequency Hearing Loss in Older Adults.

OBJECTIVE: Klotho is a protein with various biological functions, including anti-aging effects. Although research suggests Klotho plays a key role in auditory function, the relationship between serum Klotho levels and high-frequency hearing loss (HFHL) in older adults remains unclear. METHODS: We analyzed data from individuals aged 70-79 years participating in the 2009-2010 cycle of the National Health and Nutrition Examination Survey. Multivariate logistic regression models were employed to assess the relationship between serum Klotho levels and HFHL. Restricted cubic splines were utilized to evaluate linearity and examine the dose-response relationship. Additionally, we performed subgroup analyses to evaluate the consistency of this relationship across various subgroups. RESULTS: In this study of 422 elderly individuals aged 70-79 years (mean age 73.8 years, with 47.4% male participants), the median serum Klotho concentration was 754.6 pg/mL. Multivariable logistic regression analysis consistently demonstrated that higher serum Klotho levels were associated with a reduced risk of HFHL across various models (ORs: 0.24-0.32, p = 0.020-0.028). Additionally, restricted cubic spline analysis confirmed a linear negative association between serum Klotho levels and HFHL risk, with a p-value for nonlinearity of 0.474. Subgroup analyses did not reveal any statistically significant interactions modifying this relationship. CONCLUSION: Serum Klotho levels are inversely associated with the risk of HFHL. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024 Laryngoscope, 2024.

Association between the duration of smoking cessation and α-Klotho levels in the US middle-aged and elderly population.

Background: α-Klotho is a molecule associated with aging and several diseases. Previous studies have reported decreased levels of serum α-Klotho (SαKl) in smokers compared to never smokers. Interestingly, we also found the SαKl level could partly recover in those who quit smoking. The objective of this study was to investigate SαKl levels in the US population who quit smoking for a certain period. Methods: A total of 9268 participants, ranging in age from 40 to 79 years were enrolled in this cross-sectional study, 37.04 % were identified as former smoker. Data from the NHANES conducted between 2007 and 2016 were utilized for analysis. The association between the period of smoking cessation and SαKl levels was evaluated through multivariate linear regression models. Additionally, a detailed analysis stratified by key clinical factors was performed. Results: The mean level of SαKl among the former smoker was 827.41 pg/mL. After full adjustment, the SαKl level increased over time after smoking cessation, with an increase of 1.20 pg/ml per year of abstinence (P = 0.005). The linear correlation persists regardless of the duration of the smoking habit before quitting. In the stratified analysis, a positive correlation was observed between duration of smoking cessation and SαKl levels in individuals aged 60-79 years, females, normal weight individuals, those involved in moderate or vigorous physical activity, and those with a history of cancer (all P<0.05). Conclusion: This study showed a positive association between the duration of smoking cessation and SαKl levels in former smokers. Prolonged abstinence may contribute to increased SαKl levels which may protect people against aging-related diseases.

Role of Emerging Urinary Biomarkers in Predicting Progressive Deterioration of Kidney Function in Congenital Anomalies of Kidney and Urinary Tract: Trefoil Family Factor 3, Alpha Soluble Klotho and Urinary Microalbuminuria.

INTRODUCTION: Chronic kidney disease is an irreversible fate of many CAKUT (Congenital Abnormalities of the Kidneys and Urinary Tract) patients. Biomarkers involved in the disease progression are raised early in the disease process and aid in identifying the individuals at risk of progressive renal function decline. AIMS: To determine and compare the initial levels of urinary biomarkers in patients of CAKUT with asymptomatic controls and to correlate the same with progression of renal disease. RESULTS: This study includes 66 children with CAKUT and 22 healthy controls. Initial levels of three urinary Biomarkers: Trefoil family factor 3 (TFF3), Alpha soluble Klotho and Albumin-to-creatinine ratio (ACR) was recorded. Kidney function was assessed initially and at the end of 1 y follow up. Progressive deterioration of renal disease was noted in 26 (fall in GFR by >10 ml/min/m2). Median levels of urinary TFF3, alpha soluble Klotho and ACR was higher in patients with CAKUT (263, 18, 56 mcg/gCr) as compared to controls (15, 5, 6 mcg/gCr) and was further higher in patients having a progressive kidney disease (586, 40, 182 mcg/gCr). The cut-off value of the TEF3 to diagnose progressive renal disease was 178 mcg/g Cr with sensitivity and specificity of 95 % and 96 %, respectively. Using a cut-off of 29 mg/g Cr for ACR, sensitivity and specificity were 97 and 96 %, respectively. Urinary soluble Klotho was a relatively poor urinary biomarker with sensitivity and specificity of only 70 and 78 %, respectively, at a cut-off value of 18 mcg/g Cr. CONCLUSION: TFF3 and ACR are useful biomarkers which can be included in the biomarker panel to identify patients having a progressive renal disease and are at a risk of developing CKD.

Asparagine614 Determines the Transport and Function of the Murine Anti-Aging Protein Klotho.

Klotho is an anti-aging protein whose deletion significantly reduces lifespan in mice, while its over-expression increases lifespan. Klotho is a type-I transmembrane protein that is N-glycosylated at eight positions within its ectodomain. Our study demonstrates that N-glycosylation or mutation at position N614, but not at N161, N285, or N346 in mouse Klotho, is critically involved in the transport of Klotho out of the endoplasmic reticulum (ER). Consequently, while wild-type Klotho-EGFP as well as the N-glycosylation mutants N161Q, N285Q, and N346Q were present at the plasma membrane (PM), only small amounts of the N614Q Klotho-EGFP were present at the PM, with most of the protein accumulating in the ER. Protein interactome analysis of Klotho-EGFP N614Q revealed increased interactions with proteasome-related proteins and proteins involved in ER protein processing, like heat shock proteins and protein disulfide isomerases, indicative of impaired protein folding. Co-immunoprecipitation experiments confirmed the interaction of Klotho-EGFP N614Q with ER chaperons. Interestingly, despite the low amounts of Klotho-EGFP N614Q at the PM, it efficiently induced FGF receptor-mediated ERK activation in the presence of FGF23, highlighting its efficacy in triggering downstream signaling, even in limited quantities at the PM.

Genetically conditioned interaction among microRNA-155, alpha-klotho, and intra-renal RAS in male rats: Link to CKD progression.

Incident chronic kidney disease (CKD) varies in populations with hypertension of similar severity. Proteinuria promotes CKD progression in part due to activation of plasminogen to plasmin in the podocytes, resulting in oxidative stress-mediated injury. Additional mechanisms include deficiency of renal alpha-klotho, that inhibits Wnt/beta-catenin, an up regulator of intra-renal renin angiotensin system (RAS) genes. Alpha-klotho deficiency therefore results in upregulation of the intra-renal RAS via Wnt/beta-catenin. In hypertensive, Dahl salt sensitive (DS) and spontaneously hypertensive rats (SHR), we investigated renal and vascular injury, miR-155, AT1R, alpha-klotho, and TNF-α. Hypertensive high salt DS (DS-HS), but not SHR developed proteinuria, plasminuria, and glomerulosclerosis. Compared to DS low salt (DS-LS), in hypertensive DS-HS alpha-klotho decreased 5-fold in serum and 2.6-fold in kidney, whereas serum mir-155 decreased 3.3-fold and AT1R increased 52% in kidney and 77% in aorta. AT1R, alpha-klotho, and miR-155 remained unchanged in prehypertensive and hypertensive SHR. TNF-α increased by 3-fold in serum and urine of DS-HS rats. These studies unveiled in salt sensitive DS-HS, but not in SHR, a genetically conditioned dysfunction of the intermolecular network integrated by alpha-klotho, RAS, miR-155, and TNF-α that is at the helm of their end-organ susceptibility while plasminuria may participate as a second hit.

New insights into the role of Klotho in inflammation and fibrosis: molecular and cellular mechanisms.

As the body's defense mechanism against damage and infection, the inflammatory response is a pathological process that involves a range of inflammatory cells and cytokines. A healthy inflammatory response helps the body repair by eliminating dangerous irritants. However, tissue fibrosis can result from an overly intense or protracted inflammatory response. The anti-aging gene Klotho suppresses oxidation, delays aging, and fosters development of various organs. Numerous investigations conducted in the last few years have discovered that Klotho expression is changed in a variety of clinical diseases and is strongly linked to the course and outcome of a disease. Klotho functions as a co-receptor for FGF and as a humoral factor that mediates intracellular signaling pathways such as transforming growth factor ß (TGF-ß), toll-like receptors (TLRs), nuclear factor-kappaB (NF-κB), renin -angiotensin system (RAS), and mitogen-activated protein kinase (MAPK). It also interferes with the phenotype and function of inflammatory cells, such as monocytes, macrophages, T cells, and B cells. Additionally, it regulates the production of inflammatory factors. This article aims to examine Klotho's scientific advances in terms of tissue fibrosis and the inflammatory response in order to provide novel therapy concepts for fibrotic and inflammatory disorders.

Correlation of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio with serum α-klotho levels in US middle-aged and older individuals: Results from NHANES 2007-2016.

Background: The α-klotho (αKl) is widely accepted as an anti-aging and anti-inflammatory protein. However, it is rarely reported on the function and mechanism of αKl in the overall population (including healthy people and those with history of chronic disease). The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are established as predictors of systemic inflammation. This study aims to investigate the relationship between NLR, PLR, and αKl levels in the overall population. Methods: Data from 10,124 adults aged 40 years old and above, collected from NHANES 2007-2016, were analyzed. Associations between NLR, PLR, and αKl levels were assessed by weighted multivariate linear regression analyses, adjusting for potential confounders. Subgroup analysis was conducted by gender, age, diabetes, cardiovascular disease, and chronic kidney disease. Results: Weighted linear regression models showed that a significant negative correlation was observed between both NLR and PLR with αKl levels. Subgroup analysis revealed that the negative correlation between NLR and serum αKl levels was not significant in individuals aged 40-59 years and males, while this relationship remained stable across most other subgroups. The negative correlation between PLR and serum αKl levels was consistent across most subgroups but not significant in individuals with cardiovascular disease. Conclusion: Our study revealed a significant negative relationship between inflammatory markers (NLR and PLR) and serum αKl levels, suggesting systemic inflammation may be linked to reduced αKl expression. Subgroup analyses showed that the relationship varies across different demographic and health-related factors. We provided insight into the significance of managing inflammation and preserving αKl levels.

Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging.

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1ß, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-ß receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-ß on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-ß and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.

Relationship of fibroblast growth factor 21, Klotho, and diabetic retinopathy: a meta-analysis.

Background: Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus. Research has identified a close relationship between fibroblast growth factor 21 (FGF21) and DR. FGF21 is a member of the FGF subfamily, which is activated by the Klotho coenzyme involved in the occurrence of DR. However, the association between FGF21, Klotho, and DR remains controversial. Aim: To assess FGF21 and Klotho levels in patients with DR. Methods: A literature search of the Web of Science, Wiley Online Library, PubMed, China National Knowledge Infrastructure and Wanfang databases was performed. The title or abstract search terms "diabetic retinopathy" and "DR" were used in combination with "fibroblast growth factor 21", "FGF21", and "Klotho". Meta-analysis results are presented as standardized mean difference (SMD) with corresponding 95% confidence interval (CI). Results: Fifteen studies were included in this meta-analysis. FGF21 levels in patients with DR were significantly higher than in non-DR patients with diabetes (SMD: 2.12, 95% CI [1.40, 2.84]). Klotho levels in patients with DR were significantly lower than in non-DR patients with diabetes (SMD: -0.63, 95% CI [-1.22, - 0.04]). Conclusions: This systematic review is the first to evaluate the relationship between FGF21, Klotho levels, and DR. FGF21 levels were significantly higher in patients with DR. Fully elucidating the role of FGF21 will significantly contribute to the treatment of DR.

Prostaglandin E2 signaling through prostaglandin E receptor subtype 2 and Nurr1 induces fibroblast growth factor 23 production.

Bone cells produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D homeostasis, and a paracrine factor produced in further tissues. Chronic kidney disease and cardiovascular disorders are associated with early elevations of plasma FGF23 levels associated with clinical outcomes. FGF23 production is dependent on many conditions including inflammation. Prostaglandin E2 (PGE2) is a major eicosanoid with a broad role in pain, inflammation, and fever. Moreover, it regulates renal blood flow, renin secretion, natriuresis as well as bone formation through prostaglandin E receptor 2 (EP2). Here, we studied the role of PGE2 and its signaling for the production of FGF23. Osteoblast-like UMR-106 cells were exposed to EP receptor agonists, antagonists or RNAi. Wild type and EP2 knockout mice were treated with stable EP2 agonist misoprostol. Fgf23 or Nurr1 gene expression was determined by quantitative real-time PCR, hormone and further blood parameters by enzyme-linked immunosorbent assay and colorimetric methods. PGE2 and EP2 agonists misoprostol and butaprost enhanced FGF23 production in UMR-106 cells, effects mediated by EP2 and transcription factor Nurr1. A single dose of misoprostol up-regulated bone Fgf23 expression and FGF23 serum levels in wild type mice with subtle effects on parameters of mineral metabolism only. Compared to wild type mice, the FGF23 effect of misoprostol was significantly lower in EP2-deficient mice. To conclude, PGE2 signaling through EP2 and Nurr1 induces FGF23 production. Given the broad physiological and pathophysiological implications of PGE2 signaling, this effect is likely of clinical relevance.

Serum Klotho Is Elevated in Patients with Acute Myocardial Infarction and Could Predict Poor In-Hospital Prognosis.

INTRODUCTION: Klotho has emerged as a potential protective factor for cardiovascular diseases recently. Nevertheless, the levels of serum Klotho in acute coronary syndrome (ACS) have not been reported. Hence, we undertook a study to investigate the potential correlation between serum Klotho and ACS patients. METHOD: This observational cohort study was conducted at Peking University People's Hospital between May 2016 and April 2020. Upon admission, we collected the patients' clinical data and conducted ELISA tests to measure their serum Klotho levels. RESULT: A total of 349 patients were enrolled in this study, including 14 patients with UA and 335 patients with AMI. We observed that serum Klotho levels were obviously higher in the AMI group compared to the UA group (median 479.8 vs. 233.8 pg/mL, p = 0.035). In addition, serum Klotho levels were positively correlated with cardiac function and more pronounced in patients who died in the hospital (median 721.1 vs. 468.3 pg/mL, p < 0.001). A logistic regression analysis indicated that age ≥ 78 years old, HR ≥ 90 bpm, Killip classification ≥ 3 grade, and serum Klotho > 645.0 pg/mL were risk factors for poor prognosis. CONCLUSIONS: Serum Klotho is obviously increased in patients with AMI and with a positive correlation with cardiac function, and its elevation could serve as a predictor of poor prognosis in ACS patients.